Therapeutic n-aryl or n-heteroaryl pyrazolidine and pyrazolidinone derivatives

ABSTRACT

A compound having a structure 
     
       
         
         
             
             
         
       
     
     and therapeutic methods, compositions, and medicaments related thereto are disclosed herein.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/836,094, filed Aug. 8, 2007, which claims the benefit of U.S.provisional patent application Ser. No. 60/821,994, filed on Aug. 10,2006, each of which is incorporated herein by reference in its entirety.

DESCRIPTION OF THE INVENTION

Disclosed herein is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;Y is an organic acid functional group, or an amide or ester thereofcomprising up to 14 carbon atoms; or Y ishydroxymethyl or an ether thereof comprising up to 14 carbon atoms; or Yis a tetrazolyl functional group;A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein 1-CH₂— may be replaced by S or O, and1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—;U¹ and U² are independently hydrogen, O, or S;J¹ is H, O; OH; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkylhaving 1, 2, 3, 4, 5, or 6 carbon atoms; F; Cl; Br; I;

CN; or CF₃; and

B is substituted aryl or substituted heteroaryl.

Also disclosed herein is a carboxylic acid or a bioisostere thereof,said carboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein 1-CH₂— may be replaced by S or O, and1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—;U¹ and U² are independently hydrogen, O, or S;J¹ is H; O; OH; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkylhaving 1, 2, 3, 4, 5, or 6 carbon atoms; F; Cl; Br; I; CN; or CF₃; andB is substituted aryl or substituted heteroaryl.

“Bioisosteres are substituents or groups that have chemical or physicalsimilarities, and which produce broadly similar biological properties.”Silverman, Richard B., The Organic Chemistry of Drug Design and DrugAction, 2^(nd) Edition, Amsterdam: Elsevier Academic Press, 2004, p. 29.

While not intending to be limiting, organic acid functional groups arebioisoteres of carboxylic acids. An organic acid functional group is anacidic functional group on an organic molecule. While not intending tobe limiting, organic acid functional groups may comprise an oxide ofcarbon, sulfur, or phosphorous. Thus, while not intending to limit thescope of the invention in any way, in certain compounds Y is acarboxylic acid, sulfonic acid, or phosphonic acid functional group.

Additionally, an amide or ester of one of the organic acids mentionedabove comprising up to 14 carbon atoms is also contemplated. In anester, a hydrocarbyl moiety replaces a hydrogen atom of an acid such asin a carboxylic acid ester, e.g. CO₂Me, CO₂Et, etc. In anotherembodiment, in an ester, a hydroxyethyl moiety replaces a hydrogen atomof an acid, e.g., CO₂CH₂CH₂OH.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H. The following amides are also specifically contemplated,CONSO₂-biphenyl, CONSO₂-phenyl, CONSO₂-heteroaryl, and CONSO₂-naphthyl.The biphenyl, phenyl, heteroaryl, or naphthyl may be substituted orunsubstituted.

Han et. al. (Biorganic & Medicinal Chemistry Letters 15 (2005)3487-3490) has recently shown that the groups shown below are suitablebioisosteres for a carboxylic acid. The activity of compounds with thesegroups in inhibiting HCV NS3 protease was comparable to or superior tosimilar compounds where the group is replaced by CO₂H. Thus, Y could beany group depicted below.

Carboxylic Acid Bioisosteres According to Han et. al.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 14 carbonatoms. An ether is a functional group wherein a hydrogen of an hydroxylis replaced by carbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc. These groupsare also bioisosteres of a carboxylic acid.

“Up to 14 carbon atoms” means that the entire Y moiety, including thecarbonyl carbon of a carboxylic acid ester or amide, and both carbonatoms in the —CH₂O—C of an ether has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 carbon atoms.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group.

While not intending to be limiting, examples of compounds having theidentified Y are depicted below. In these examples R is H orhydrocarbyl, subject to the constraints defined herein. Each structurebelow represents a specific embodiment which is individuallycontemplated, as well as pharmaceutically acceptable salts and prodrugsof compounds which are represented by the structures. However, otherexamples are possible which may not fall within the scope of thestructures shown below.

Organic Acids Esters Amides M¹—CO₂H M¹—CO₂R M¹—CO₂NR₂ Carboxylic AcidCarboxylic Acid Ester Carboxylic Acid Amide M¹—P(O)(OH)₂ M¹—P(O)(OH)RM¹—P(O)(OH)NR₂ Phosponic Acid Phosphonic Acid Ester Phosphonic AcidAmide M¹—SO₃H M¹—SO₃R M¹—SO₃NR₂ Sulfonic Acid Sulfonic Acid EsterSulfonic Acid Amide M¹—CH₂OH M¹—CH₂OR Y is hydroxymethyl Ether

A tetrazolyl functional group is another bioisostere of a carboxylicacid. An unsubstituted tetrazolyl functional group has two tautomericforms, which can rapidly interconvert in aqueous or biological media,and are thus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

While not intending to limit the scope of the invention in any way, inone embodiment, Y is CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂,CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

According to Silverman (p. 30), the moieties shown below are alsobioisosteres of a carboxylic acid.

Carboxylic Acid Bioisosteres According to Silverman

Orlek et al. (J. Med. Chem. 1991, 34, 2726-2735) described oxadiazolesas suitable bioisosteres for a carboxylic acid. These ester replacementswere shown to be potent muscarinic agonists having improved metabolicstability. Oxadiazoles were also described by Anderson et al. (Eur. J.Med. Chem. 1996, 31, 417-425) as carboxamide replacements havingimproved in vivo efficacy at the benzodiazepine receptor.

Carboxylic Acid Bioisosteres According to Orlek et. al

Kohara et al. (J. Med. Chem. 1996, 39, 5228-5235) described acidicheterocycles as suitable bioisosteres for a tetrazole. These carboxylicacid replacements were shown to be potent angiotensin II receptorantagonists having improved metabolic stability.

Tetrazole Bioisosteres According to Kohara et. al.

Drysdale et al. (J. Med. Chem. 1992, 35, 2573-2581) have describedcarboxylic acid mimics of non-peptide CCK-B receptor antagonists. Thebinding affinities of many of the bioisosteres are similar to the parentcarboxylic acid.

Carboxylic Acid Bioisosteres According to Drysdale et. al.

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein 1-CH₂— may be replaced by S or O, and1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—.

Thus, A may be —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S or O. For example, A maybe a moiety where S replaces one or two carbon atoms such as one of thefollowing or the like.

Alternatively, A may be a moiety where O replaces one or two carbonatoms such as one of the following or the like.

Alternatively, A may have an O replacing one carbon atom and an Sreplacing another carbon atom, such as one of the following or the like.

Alternatively, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein 1-CH₂— may be replaced by S or O, and1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—. In other words, in oneembodiment A comprises:

-   -   1) a) 1, 2, 3, or 4-CH₂— moieties, or        -   b) 0, 1 or 2-CH₂— moieties and —CH═CH— or —C≡C—; and    -   2) Ar;    -   e.g. —CH₂—Ar—, —(CH₂)₂—Ar—, —CH═CH—Ar—, —C≡C—Ar—, —CH₂—Ar—CH₂—,        —CH₂Ar—(CH₂)₂—, —CH₂Ar—CH═CH—, —CH₂Ar—C≡C—, —(CH₂)₂—Ar—(CH₂)₂—,        and the like;        in another embodiment A comprises:    -   1) a) O; and 0, 1, 2, or 3-CH₂-moieties; or        -   b) O; and 0 or 1-CH₂— moieties and —CH═CH— or —C≡C—; and    -   2) Ar;    -   e.g., —O—Ar—, —Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —OAr—CH═CH—,        —O—Ar—C≡C—, —O—CH₂—Ar—, —O—CH₂—Ar—(CH₂)₂, —O—CH₂Ar—CH═CH—,        —O—CH₂Ar—C≡C—, and the like; or        in another embodiment A comprises:    -   1) a) S; and 0, 1, 2, or 3-CH₂— moieties; or        -   b) S; and 0 or 1-CH₂— moieties and —CH═CH— or —C≡C—; and    -   2) Ar;    -   e.g., —S—Ar—, —Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —SAr—CH═CH—,        —S—Ar—C═C—, —S—CH₂—Ar—, —S—CH₂—Ar—(CH₂)₂, —S—CH₂Ar—CH═CH—,        —S—CH₂Ar—C≡C—, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O and 1-CH₂—CH₂— may be replaced by —CH═CH— or—C≡C—.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O and 1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O or 1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O and 1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. Substitutents of Ar each have from0 to 4 carbon atoms, from 0 to 3 oxygen atoms, from 0 to 2 sulfur atoms,from 0 to 2 nitrogen atoms, from 0 to 3 fluorine atoms, from 0 to 1chlorine atoms, from 0 to 1 bromine atoms, from 0 to 1 iodine atoms, andfrom 0 to 10 hydrogen atoms.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂-Ph-OCH₂—. In another embodiment, Ph is attached at the 1 and 3positions, otherwise known as m-interphenylene, such as when A has thestructure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one —CH₂— may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In one embodiment, Ar is thienyl.

In other embodiments, A has one of the following structures.

In another embodiment A is —CH₂OCH₂Ar—.

In another embodiment A is —CH₂SCH₂Ar—.

In another embodiment A is —(CH₂)₃Ar—.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂S(CH₂)₄—.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis-CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh isinterphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-(methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl).

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺ salt. Any cation of thesalt is not counted in the “4 or less heavy atoms.” Thus, thesubstituent may be

hydrocarbyl having up to 4 carbon atoms, including alkyl up to C4,alkenyl, alkynyl, and the like;hydrocarbyloxy up to C3;organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and saltsthereof;

CF₃;

halo, such as F, Cl, or Br;hydroxyl;NH₂ and alkylamine functional groups up to C₃;other N or S containing substituents such as CN, NO₂, and the like;and the like.

In one embodiment A is —(CH₂)_(m)-Ph-(CH₂)_(o)— wherein the sum of m ando is 1, 2, or 3, and wherein one CH₂ may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂-Ph-OCH₂—. In another embodiment, Ph is attached at the 1 and 3positions, otherwise known as m-interphenylene, such as when A has thestructure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂—O—(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below, andpharmaceutically acceptable salts thereof, and prodrugs thereof, arecontemplated as individual embodiments. In other words, each structurerepresents a different embodiment.

J1 is H; O; OH; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkylhaving 1, 2, 3, 4, 5, or 6 carbon atoms; F; Cl; Br; I; CN; or CF3. Thus,each structure depicted below represents a compound embodiment which isindividually contemplated. Pharmaceutically acceptable salts andprodrugs of compounds according to the structures below are alsocontemplated.

U1 and U2 are independently hydrogen, O, or S. Thus, each structuredepicted below represents a compound embodiment which is individuallycontemplated. Pharmaceutically acceptable salts and prodrugs ofcompounds according to the structures below are also contemplated.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺salt. Thus, while not intending to limit the scope of the invention inany way, a substituent may be:

hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen suchas alkyl, alkenyl, alkynyl, and the like, including linear, branched orcyclic hydrocarbyl, and combinations thereof;hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,O-cyclohexyl, etc, up to 19 carbon atoms;other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the like;thioether substituents including S-hydrocarbyl and other thioethersubstituents;hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,etc, up to 19 carbon atoms;nitrogen substituents such as NO₂, CN, and the like, includingamino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like;carbonyl substituents, such as CO₂H, ester, amide, and the like;halogen, such as chloro, fluoro, bromo, and the likefluorocarbyl, such as CF₃, CF₂CF₃, etc.;phosphorous substituents, such as PO₃ ²⁻, and the like;sulfur substituents, including S-hydrocarbyl, SH, SO₃H, SO₂-hydrocarbyl,SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl. For this type ofpolycyclic ring system, an aromatic or heteroaromatic ring, not anon-aromatic ring, must be attached to the remainder of the molecule,i.e. the part of the molecule that is not B. In other words, in anystructure depicting —B herein, where — is a bond, the bond is a directbond to an aromatic ring.

In one embodiment, B is substituted aryl or heteroaryl.

In another embodiment B is substituted phenyl.

In another embodiment B has no halogen atoms.

In another embodiment B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxybutyl)phenyl.

In another embodiment B is 4-(1-hydroxyheptyl)phenyl.

In another embodiment B is 4-(1-hydroxyhexyl)phenyl.

In another embodiment B is 4-(1-hydroxypentyl)phenyl.

In another embodiment B is 4-(1-hydroxypropyl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

In another embodiment B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

In another embodiment B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-tert-butylphenyl.

In another embodiment B is 4-hexylphenyl.

In another embodiment B is 4-(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxycyclobutyl)phenyl.

In another embodiment B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

In another embodiment B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

In another embodiment B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

In another embodiment B is 4-(cyclohexylmethyl)phenyl.

In another embodiment B is 4-(hydroxy(phenyl)methyl)phenyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:

linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; andalkyl fragments consisting of both cyclic and noncyclic components,whether linear or branched, which may be attached to the remainder ofthe molecule at any available position including terminal, internal, orring carbon atoms.

Alkenyl is hydrocarbyl having one or more double bonds including

linear alkenyl, branched alkenyl, cyclic alkenyl, and combinationsthereof in analogy to alkyl.

Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like. Aryl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.

Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule. Examples are—CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may not behydrocarbyl, depending upon whether the aryl portion has substituentswith heteroatoms.

Unconjugated dienes or polyenes have one or more double bonds which arenot conjugated. They may be linear, branched, or cyclic, or acombination thereof.

Combinations of the above are also possible.

Thus, each of the structures below is contemplated. These structures, orpharmaceutically acceptable salts thereof, or prodrugs thereof,individually represent a compound which is an embodiment contemplatedherein. In other words, each structure represents a differentembodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

Hypothetical examples of useful compounds are shown below.

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;Y is an organic acid functional group, or an amide or ester thereofcomprising up to 14 carbon atoms; or Y ishydroxymethyl or an ether thereof comprising up to 14 carbon atoms; or Yis a tetrazolyl functional group;A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein 1-CH₂— may be replaced by S or O, and1-CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—;U¹ and U² are independently hydrogen, O, or S;J¹ is H; O; OH; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkylhaving 1, 2, 3, 4, 5, or 6 carbon atoms; F; Cl; Br; I;

CN; or CF₃; and

B is substituted aryl or substituted heteroaryl.

Compound Example 2

The compound according to compound example 1 wherein Y is selected fromCO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH,P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NH R²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

Compound Example 3

The compound according to compound example 1 or 2 wherein B issubstituted phenyl.

Compound Example 4

The compound according to compound example 1 or 2 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 5 The compound according to compound example 4 whereinR is alkyl. Compound Example 6

The compound according to compound example 4 wherein R is arylalkyl.

Compound Example 7

The compound according to compound example any one of compound examples1 to 6 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 8

The compound according to compound example 1 or 2 wherein A is(3-methylphenoxy)methyl.

Compound Example 9

The compound according to compound example 1 or 2 wherein A is(4-but-2-ynyloxy)methyl.

Compound Example 10

The compound according to compound example 1 or 2 wherein A is2-(2-ethylthio)thiazol-4-yl.

Compound Example 11

The compound according to compound example 1 or 2 wherein A is2-(3-propyl)thiazol-5-yl.

Compound Example 12

The compound according to compound example 1 or 2 wherein A is3-methoxymethyl)phenyl.

Compound Example 13

The compound according to compound example 1 or 2 wherein A is3-(3-propylphenyl.

Compound Example 14

The compound according to compound example 1 or 2 wherein A is3-methylphenethyl.

Compound Example 15

The compound according to compound example 1 or 2 wherein A is4-(2-ethyl)phenyl.

Compound Example 16

The compound according to compound example 1 or 2 wherein A is4-phenethyl.

Compound Example 17

The compound according to compound example 1 or 2 wherein A is4-methoxybutyl.

Compound Example 18

The compound according to compound example 1 or 2 wherein A is5-(methoxymethyl)furan-2-yl.

Compound Example 19

The compound according to compound example 1 or 2 wherein A is5-(methoxymethyl)thiophen-2-yl.

Compound Example 20

The compound according to compound example 1 or 2 wherein A is5-(3-propyl)furan-2-yl.

Compound Example 21

The compound according to compound example 1 or 2 wherein A is5-(3-propyl)thiophen-2-yl.

Compound Example 22

The compound according to compound example 1 or 2 wherein A is 6-hexyl.

Compound Example 23

The compound according to compound example 1 or 2 wherein A is(Z)-6-hex-4-enyl.

Compound Example 24

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

Compound Example 25

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

Compound Example 26

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 27

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxybutyl)phenyl.

Compound Example 28

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxyheptyl)phenyl.

Compound Example 29

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxyhexyl)phenyl.

Compound Example 30

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxypentyl)phenyl.

Compound Example 31

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxypropyl)phenyl.

Compound Example 32

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

Compound Example 33

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

Compound Example 34

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

Compound Example 35

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 2,3-dihydro-1H-inden-5-yl.

Compound Example 36

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 37

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

Compound Example 38

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 39

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-tert-butylphenyl.

Compound Example 40

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-hexylphenyl.

Compound Example 41

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 42

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

Compound Example 43

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxycyclobutyl)phenyl.

Compound Example 44

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

Compound Example 45

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

Compound Example 46

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

Compound Example 47

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(cyclohexylmethyl)phenyl.

Compound Example 48

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(hydroxy(phenyl)methyl)phenyl.

Compound Example 49

The compound according to any one of compound examples 1 to 48 whereinJ¹ is H.

Compound Example 50

The compound according to any one of compound examples 1 to 48 whereinJ¹ is O.

Compound Example 51. The compound according to any one of compoundexamples 1 to 48 wherein J¹ is OH. Compound Example 52

The compound according to any one of compound examples 1 to 48 whereinJ¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 53

The compound according to any one of compound examples 1 to 48 whereinJ¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

Compound Example 54

The compound according to any one of compound examples 1 to 48 whereinJ¹ is F.

Compound Example 55

The compound according to any one of compound examples 1 to 48 whereinJ¹ is Cl.

Compound Example 56

The compound according to any one of compound examples 1 to 48 whereinJ¹ is Br.

Compound Example 57

The compound according to any one of compound examples 1 to 48 whereinJ¹ is 1.

Compound Example 58

The compound according to any one of compound examples 1 to 48 whereinJ¹ is CN.

Compound Example 59

The compound according to any one of compound examples 1 to 48 whereinJ¹ is CF₃,

Compound Example 60

The compound according to any one of compound embodiments 1 to 59wherein U¹ is H.

Compound Example 61

The compound according to any one of compound embodiments 1 to 59wherein U¹ is O.

Compound Example 62

The compound according to any one of compound embodiments 1 to 59wherein U¹ is S.

Compound Example 63

The compound according to any one of compound embodiments 1 to 62wherein U² is H.

Compound Example 64

The compound according to any one of compound embodiments 1 to 62wherein U² is O.

Compound Example 65

The compound according to any one of compound embodiments 1 to 62wherein U² is S.

The following are hypothetical examples of compositions, kits, methods,uses, and medicaments employing the hypothetical compound examples.

COMPOSITION EXAMPLE

A composition comprising a compound according to any one of compoundexamples 1 to 65, wherein said composition is a liquid which isophthalmically acceptable.

MEDICAMENT EXAMPLES

Use of a compound according to any one of compound examples 1 to 65 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

Use of a compound according to any one of compound examples 1 to 65 inthe manufacture of a medicament for the treatment of baldness in aperson.

A medicament comprising a compound according to any one of compoundexamples 1 to 65, wherein said composition is a liquid which isophthalmically acceptable.

METHOD EXAMPLE

A method comprising administering a compound according to any one ofcompound examples 1 to 65 to a mammal for the treatment of glaucoma orocular hypertension.

KIT EXAMPLE

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 65, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C8981(i.e. the terminal carboxylic acid of a natural prostaglandin), or anester may be derived from a carboxylic acid functional group on anotherpart of the molecule, such as on a phenyl ring. While not intending tobe limiting, an ester may be an alkyl ester, an aryl ester, or aheteroaryl ester. The term alkyl has the meaning generally understood bythose skilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

Synthetic Methods

While there are many ways the compounds disclosed herein, one exemplarysynthesis may begin with commercially available N-Boc hydrazine (1, alsoknown as t-butyl carbazate, Aldrich Chemical Company, see Scheme 1).N-arylation occurs to give 2 according to Buchwald's copper-catalyzedprocedure (Org. Lett. 2001, 3, 3803-3805) using a wide variety ofsubstituted bromophenyl and other bromoaryl compounds a. The haloarenesa are either available commercially or may be made according topublished literature procedures. For example, U.S. patent applicationSer. No. 11/009,298, filed on Dec. 10, 2004 and U.S. Provisional PatentApplication 60/742,779 filed on Dec. 6, 2005, both of which areexpressly incorporated by reference herein, disclose methods of making anumber of useful substituted bromophenyl compounds. These procedures mayalso be readily adapted to other bromoaryl compounds such as substitutedbromothienyl, substituted bromofuryl, substituted bromopyridinyl,substituted bromonaphthyl, substituted bromobenzothienyl, and the like.Intermediate 2 is then alkylated on N′ using electrophiles b to provideintermediate 3.

Examples of b include ethyl 7-bromoheptanoate (commercially availablefrom Aldrich Chemical Company) and methyl 7-bromohept-5-ynoate (Org.Synth. 1993, Collect. Vol. VIII, 415-420). Examples of b also includeelectrophiles bearing aryl and heteroaryl groups (e.g. methyl4-(2-bromoethyl)benzoate [available in one step from commerciallyavailable 4-(2-bromoethyl)benzoic acid] and methyl5-(3-bromopropyl)-thiophene-2-carboxylate [see WO 2004/037786,incorporated by reference herein]). Other methods of preparing b arereadily ascertained by those of ordinary skill in the art based uponthis disclosure.

Intermediate 3 is then deprotected to give intermediate 4 which istreated with 3-chloropropionyl chloride (using the method of Araldi, etal., US 2004/0254233) to give product 5. Compound 5 may be the targetcompound, or may require deprotection(s) and/or functionalization(depending on the nature of B and Y) to arrive at the target compound.

In another hypothetical example, benzophenone hydrazone (6, Aldrichchemical company) serves as the stating material (see Scheme 2). In thiscase, N′-arylation occurs to give 7 according to Buchwald'spalladium-catalyzed procedure (J. Am. Chem. Soc. 1998, 120, 6621-6622)using a wide variety of substituted bromophenyl and other bromoarylcompounds a. Deprotection reveals the aryl hydrazine 8 which isprotected to give N-Boc-N′-aryl hydrazine 9. A large variety ofsubstituted aryl hydrazines such as 8 are commercially available.Treatment of 9 with 3-chloropropionyl chloride (using the method ofAraldi, et al., US 2004/0254233) gives intermediate 10 which is thendeprotected and alkylated on nitrogen to afford product 12. Compound 12may be the target compound, or may require deprotection(s) and/orfunctionalization (depending on the nature of B and Y) to arrive at thetarget compound.

Intermediates 2 and 9 are regioisomers. In certain cases, the copperchemistry used to arrive at 2 will also afford compound 9 (see Buchwald,above, and Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729).Palladium-catalyzed arylation may also afford mixtures of regioisomers(Wang, et al., Tetrahedron Lett. 1999, 40, 3543-3546), mainly favoringisomer 2. This represents an alternative approach to compound 9.

In another hypothetical example (scheme 3), intermediate 3 may becyclized using malonyl chloride (or other activated source of malonate)to afford the pyrazolidine dione 13. This may be the target compound, ormay serve as an intermediate to compounds substituted at the carbonadjacent to both ketones such as 14. The ring methylene of dione 13 isalkylated using alkyl electrophiles J by employing a mild base such aspotassium carbonate using the method of Vennerstrom and Holmes, J. Med.Chem. 1987, 30, 563-567. Chlorination (J=Cl) may be accomplished usingthe method of Pesin et al. Z. Obshch. Khim. 1958, 20, 2816-2820. Otherelectrophiles known in the art can be envisioned to introduce other Jgroups (e.g. the Davis oxaziridine reagent or other suitable reagent forJ=OH and Br₂ or NBS for J=Br). As an alternative, J may be introducedinto the malonate derivative prior to reaction with compound 4. Ashalogens such as Cl and Br are useful as nucleophilic substitutionleaving groups, they provide a means for reaching other J groups usingthe nucleophile J⁻ or a synthetic equivalent thereof. Compounds whereinJ is OH may also be derivatized with triflate, tosylate, or the like toprovide good leaving groups for nucleophilic substitution. For example,J=CN may be reached in this manner. These procedures are well known inthe art.

The carbon adjacent to the ketone in pyrazolidinones 5 and 12 may bealkylated using alkyl electrophiles J by employing LDA as the base (e.g.Hiasta et al., J. Med. Chem. 1991, 34, 1560-1570) (Scheme 4). Other Jgroups may be introduced using LDA and the electrophiles discussed abovefor scheme 3. As an alternative, J may be introduced into thechloropropionate derivative prior to reaction with compound 4 orcompound 9.

A carbonyl oxygen may be replaced with sulfur using Lawesson's reagentor other methods. Thus, compounds wherein J¹, U¹ and/or U² are S may beprepared.

The steps of these synthetic procedures may also be rearranged. Forexample in Scheme 1, N′-alkylation may take place prior to amideN-arylation. It is also envisioned that chloro- or iodo-arenes may beemployed in place of the bromoarenes described above. The requisitechloro- or iodo-arenes may be prepared by procedures analogous to thoseused to prepare the bromoarenes. Alternative starting materials to N-Bochydrazine and benzophenone hydrazone include commercially available3-pyrazolidinone HCl (see Scheme 5 and example 1) and 3,5-pyrazolidinedione.

EXAMPLE 1 5-(3-(2-(4-(1-hydroxyhexyl)phenyl)-3-oxopyrazolidin-1-yl)propyl)thiophene-2-carboxylic acid (25)

Step 1. Alkylation of 20 with 21 to give 22

Potassium carbonate (8.28 g, 60.0 mmol), methyl5-(3-bromopropyl)-thiophene-2-carboxylate (21, for preparation, seeBillot, X. et al WO2004/037786, incorporated by reference herein, 5.66g, 21.5 mmol), 3-pyrazolidinone HCl (20, 2.57 g, 21.0 mmol) and DMF (25mL) were combined under argon and stirred at rt. After 3 d at rt, HPLCanalysis indicated the reaction to be complete and EtOAc (100 mL) wasadded. The mixture was washed with water (2×75 mL). The combined aqueousphase was back-extracted with EtOAc (50 mL). The combined organic phasewas washed with brine (75 mL), filtered through filter paper andconcentrated in vacuo to afford 7.5 g of a crude oil. Purification ofthe crude product by flash column chromatography on 75 g silica gel (50%CH₂Cl₂/hexane→CH₂Cl₂→20% EtOAc/CH₂Cl₂→100% EtOAc→10% MeOH/EtOAc,gradient) afforded 3.2 g (57%) of 22 which solidified on standing.

Step 2. Arylation of 22 with 23 to give 24

Cesium carbonate (4.89 g, 15.0 mmol), copper (I) iodide (19 mg, 0.10mmol), 1,10-phenanthroline (180 mg, 1.0 mmol), amide 22 (2.88 g, 10.7mmol) and 1-(4-iodophenyl)hexan-1of (23, prepared from4-iodobenzaldehyde using the method described for the analogousbromoarene in Old and Dinh, WO2006/098918, 3.34 g 11.0 mmol) and DMF (25mL) were combined into a sealable tube. Argon was bubbled through themixture for 15 min, the tube was sealed, and the mixture was heated at80° C. overnight. Upon cooling, HPLC analysis showed no reaction hadtaken place. More copper (I) iodide (60 mg, 0.32 mmol) and1,10-phenanthroline (180 mg, 1.0 mmol) was added and the mixture washeated at 80° C. overnight. Upon cooling, HPLC analysis showed thereaction was nearly complete. EtOAc (100 mL) was added and the mixturewas filtered through 25 g silica gel, washing the pad with EtOAc (150mL). The filtrate was concentrated in vacuo to afford 3.7 g of a crudeoil. Purification of the crude product by flash column chromatography on50 g silica gel (hexane→25% CH₂Cl₂/hexane→CH₂Cl₂→5% EtOAc/CH₂Cl₂→25%EtOAc/CH₂Cl₂, gradient) afforded 0.29 g (6%) of 24 as a brown oil.

Step 3. Saponification of 24 to give 25

Lithium hydroxide (0.22 mL of a 1.0 M aqueous solution, 0.22 mmol) wasadded to a solution of ester 24 (20 mg, 0.045 mmol) in THF (0.22 mL).The solution was heated at 40° C. for 18 h, then cooled to rt. Themixture was partitioned between 1.0 M HCl (1 mL) and EtOAc (5 mL). Thephases were separated and the aqueous phase was extracted with EtOAc(2×5 mL). The combined extracts were washed with brine (5 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of the cruderesidue by column chromatography on 4 g silica gel (CH₂Cl₂→20%MeOH/CH₂Cl₂) afforded 11 mg (57%) of the title compound.

Based upon this disclosure, numerous other ways of preparing thecompounds disclosed herein will be apparent to a person of ordinaryskill in the art.

In Vitro Testing

U.S. patent application Ser. No. 11/553,143, filed on Oct. 26, 2006,incorporated by reference herein, describes the methods used to obtainthe in vitro data in the table below.

EP2 data EP4 data Other Receptors (EC50 in nM) flipr cAMP fliprStructure EC50 EC50 Ki EC50 KI hFP hEP1 hEP3A hTP hIP hDP

79 1.8 251 NT >10000 NA NA 5068 NA NA NA

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound which is a carboxylic acid or a bioisostere thereof, saidcarboxylic acid having a structure

or a pharmaceutically acceptable salt thereof; wherein a dashed linerepresents the presence or absence of a bond; A is —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms maybe replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4,and wherein 1-CH₂— may be replaced by S or O, and 1-CH₂—CH₂— may bereplaced by —CH═CH— or —C≡C—; U¹ and U² are independently hydrogen, O,or S; J¹ is H; O; OH; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; F; Cl; Br; I; CN; or CF₃;B is substituted aryl or substituted heteroaryl; and R is C₁-C₆ alkyl or—CH₂CH₂OH.
 2. The compound of claim 1 wherein Y is selected from CO₂R²,CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.
 3. The compound of claim 1 wherein A has astructure selected from:


4. The compound of claim 1 wherein A is 5-(3-propyl)thiophen-2-yl,6-hexyl, or (Z)-6-hex-4-enyl.
 5. The compound of claim 1 wherein B issubstituted phenyl.
 6. The compound of claim 1 wherein R is isopropyl or—CH₂CH₂OH.
 7. The compound of claim 1 having a structure

or a pharmaceutically acceptable salt thereof; wherein R₃ is hydrogen orC₁₋₁₀ hydrocarbyl.
 8. The compound of claim 7 wherein R is isopropyl or—CH₂CH₂OH.
 9. The compound of claim 1 having a structure

or a pharmaceutically acceptable salt thereof; wherein R₃ is hydrogen orC₁₋₁₀ hydrocarbyl.
 10. The compound of claim 1 wherein J is H.
 11. Thecompound of claim 10 wherein U¹ is H.
 12. The compound of claim 11wherein U² is O.
 13. The compound of claim 9 wherein R is isopropyl or—CH₂CH₂OH.
 14. A method comprising administering a compound of claim 1to a mammal for the treatment of glaucoma or ocular hypertension.
 15. Akit comprising a composition comprising compound of claim 1, acontainer, and instructions for administration of said composition to amammal for the treatment of glaucoma or ocular hypertension.
 16. Acomposition comprising a compound of claim 1, wherein said compositionis a liquid which is ophthalmically acceptable.
 17. A method comprisingadministering a compound of claim 1 to a mammal for the treatment ofglaucoma or ocular hypertension.